Addressing threats to health care's core values, especially those stemming from concentration and abuse of power. Advocating for accountability, integrity, transparency, honesty and ethics in leadership and governance of health care.

Wednesday, January 16, 2008

Why Should Patients Continue to Take Ezetimibe?: More Fallout from the ENHANCE Trial

We have posted before (as have many others, see below) about problems with the ENHANCE trial of ezetimibe (Zetia, by Schering-Plough, and one component of Vytorin, by Merck), and how the trial was designed and implemented seemed meant to increase the likelihood of a favorable result for the sponsors' interests. Particularly controversial was the sponsors' decision to change the definition of the trial's outcome variable after the data was collected. That decision was then reversed. Later, it turned out that this decision was at the behest of a supposedly "independent" panel, but one which included a majority of members who had previous financial ties to Merck and/or Schering-Plough.

Under intense media pressure, the results of this study were just released. As summarized by theHeart.org, they showed no statistically significant improvement in the thickness of arterial walls for patients who received ezetimibe, and no statistically significant decrease in the rates of revascularization, stroke, myocardial infarction (heart attack), or cardiovascular death in the group of patients given the drug. (The study was not big enough to have much statistical power to detect such an improvement, but the rates of all these outcomes except stroke were actually greater in the ezetimibe group.)

Up until the the release of these results, no study had shown that ezetimibe produces any clinical benefit, e.g., prevents heart attacks or strokes, prolongs life, etc. And the long-delayed results of the ENHANCE trial again showed no such benefit. Thus, why should any patient take this drug? Perhaps there is an argument that patients with pre-existing coronary artery disease with elevated cholesterol and who cannot tolerate a "statin" could use ezetimibe as a last resort, and with caution even then.

So it was surprising to see two major organizations dedicated to fighting heart disease so quickly rush to defend the use of ezetimibe. First, as posted by Ed Silverman on the PharmaLot blog, the American College of Cardiology (ACC) issued a statement that mainly warned physicians not to take patients off ezetimibe nor make "major clinical decisions" based upon the new study.

Soon after the ACC statement was released, Ed Silverman also blogged that the American Heart Association issued its own statement. In it, AHA president Dr Daniel W Jones also warned against precipitously stopping ezetimibe (again, despite a complete lack of evidence that the drug does patients any good.)

Why were both reports so concerned with keeping patients on a drug that had never been shown to be of benefit? The answer is not clear.

However, Ed Silverman also noted that the ACC report "was drafted by an unnamed group of ACC leaders and so-called prevention experts, and approved by the ACC president. Among those involved was Roger Blumenthal, a professor of medicine at Johns Hopkins University, who chairs the ACC’s committee on prevention of cardiovascular disease. However, Blumenthal is also on the speaker’s bureau for Merck and Schering-Plough, and has received unspecified research grants from Merck." There is also evidence that the ACC at least was previously supported by Merck. The Center for Science in the Public Interest reported that the ACC Foundation received $500,000 - $749,999 from Merck in 2002. (So far I have not been able to find any newer information about corporate sponsorship of the ACC or its foundation, one way or the other.)

Furthermore, not acknowledged in the AHA statement was Dr Jones' previous financial ties to Merck. He disclosed in the 2003 JAMA publication of the JNC 7 report that he was a consultant for the company. [Chobanian AV, Bakris GL, Black HR et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560-2572. Link here.] Furthermore, the American Heart Association receives substantial current funding from Merck and Merck/Schering-Plough. In its 2007 report, both corporations were listed as donors in the $1,000,000 -4,999,999 range.

So this case has many lessons. It is yet another reminder of the pervasive web of conflicts of interest that entangles so many physicians, medical academics, physicians' organizations, and other health care non-profit groups.

For the final words, let me quote Dr Stefan Kertesz, who was commenting on the pervasiveness of conflicts of interest affecting the 2004 National Cholesterol Education Panel guidelines that suggested drastic lowering of cholesterol for patients with heart disease and diabetes. (Hat tip for this to DB's Medical Rants.) These controversial guidelines may be one reason physicians feel compelled to use drugs to lower cholesterol which have, like ezetimibe, no proven independent benefits for their patients.

I'm not suggesting that these experts have opinions for sale. The problem is that when data are conflicting, wishful thinking and commercial interests may supplant a rational consideration of the facts.

To protect patients we need to do two things:

We should demand entirely public disclosure of the financial ties for any expert who helps define the standards for quality in health care. And we should demand that at least some of our experts come from outside the industry, altogether.

The point is this: The science of drug development and the science of quality in health care represent two very different enterprises. If we continue to let the drug developers have such a strong hand in defining quality, we will continue to fall prey to conjecture, to wishful thinking and hype. It would be best for our health to keep these two enterprises separate.

3 comments:

As a former director of a biomedical library supporting R&D in pharma, I wonder if the discovery scientists behind development of this drug had full access to the biomedical literature and to the informatics tools to locate and retrieve them, which are very expensive, and/or the human information specialists (a.k.a. library science professionals) who are far better than most scientists and any computer system at ferreting out needed information. Pharmas have been downsizing and/or eliminating libraries and the humans staffing them - myself included (laid off 2003).

Perhaps there was (and is) literature suggesting why statins, which inhibit cholsterol synthesis in the liver, might create better clinical outcomes that ezetimibe, which acts by decreaing cholesterol absorption in the intestine.

I cannot explain why this is the case, but there are studies showing that ezetimibe does not improve endothelial function and that statins do. My teenage daughter has heterozygous familial hypercholesterolemia. Her doctors keep trying to get me to agree to giving her ezetimibe as an add-on to lovastatin. This kind of pisses me off. I should not have to argue with these cardiologists every time we see them. Let them write CYA all over my daughter's file and be done with it.I note also that the pediatric cardiologist that chaired the group that wrote the latest guidelines (3/07) for kids with "high-risk lipid abnormalities" has ties to several drug companies. I actually agree with the general thrust of the guidelines, which is to use statins as first line therapy instead of bile acid sequestrants. Certain details I disagree with, but I doubt anyone reading this would be interested so I won't go into that.

Further to my previous comment, here is the citation for the guidelines: McCrindle et al, Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents: A Scientific Statement From the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, With the Council on Cardiovascular Nursing (Circulation. 2007;115:1948-1967) Brian W. McCrindle, MD, MPH, chair of the writing group, disclosed research grants from Schering-Plough, AstraZeneca and Sankyo and Speakers Bureau/Honoraria from AstraZeneca and Merck. The guidelines recommend drug therapy starting at age 10 in boys and after menses in girls if LDL exceeds 190 or exceeds 160 with family history of premature CVD or 2 or more other risk factors. The "minimal" LDL treatment goal is 130 or 110"ideally." These cutpoints and goals can be modified if there are other risk factors. The main problem I have with this is that my daughter's LDL started at 246 so getting to a goal of 130 is very, very difficult. Since she is a girl and is only 14 I do not see the need to treat her that aggressively.

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